Loss of the TAM receptor Mer contributes to Sjögren’s syndrome-like disease in mice

Abstract

Abstract Sjögren’s syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands where the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here we report that soluble Mer (sMer) levels were elevated in SjS patient sera and positively correlated with focus score, ocular staining scores, rheumatoid factor, and Ro60 autoantibody levels. Increased sMer was also detected in C57BL/6.NOD-Aec1Aec2 (SjSS) mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage of Mer, and inactivation of such. Mer signaling outcomes were observed to be diminished in SjSS mice as evidenced by impaired efferocytosis in SjSS mouse macrophages and decreased Socs1 and Socs3 expression in SjSS salivary gland (SG). SjS diagnostic criteria were examined in MerKO mice to evaluate the protective role of Mer in SjS disease pathogenesis. MerKO mice developed SG infiltrates of B and T lymphocytes, SG apoptotic cells, antinuclear antibodies, and reduced saliva flow. Together, our data suggest a sequence of events where enhanced ADAM17 activity increases Mer inactivation, depresses Mer signaling, and removes a protection against the loss of self-tolerance and onset of autoimmune disease in SjSS mice.